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Carcinogenesis Advance Access first published online on November 9, 2005
This version published online on November 15, 2005
Carcinogenesis, doi:10.1093/carcin/bgi264
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received July 29, 2005
Revised November 1, 2005
Accepted November 2, 2005

CARCINOGENESIS

Defined genetic events associated with the spontaneous in vitro transformation of E1A/Ras-expressing human IMR90 fibroblasts

Douglas X. Mason 1 #, Daniel Keppler 2 #, Jun Zhang 3, Tonya J. Jackson 4, Yvette R. Seger 5, Seiichi Matsui 6, Fleurette Abreo 7, John K. Cowell 6, Gregory J. Hannon 8, Scott W. Lowe 8, and Athena W. Lin 4 *

1 Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, New York; Current Address: ZeptoMetrix Corporation, 872 Main Street, Buffalo, NY 14202
2 Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center, Shreveport, Louisiana; Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana
3 Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center, Shreveport, Louisiana
4 Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, New York
5 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Current Address: FasterCures, The Center For Accelerating Medical Solutions, 509 7th Street, Washington, D.C. 20004
6 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York
7 Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
8 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York

* To whom correspondence should be addressed.
Athena W. Lin, E-mail: Athena.Lin{at}roswellpark.org


  Abstract

In contrast to rodent cells, normal human fibroblasts are generally resistant to neoplastic transformation in vitro. Here, we report the derivation and characterization of a spontaneously transformed cell line from normal human IMR90 fibroblasts transduced with E1A and Ras oncogenes. Unlike the parental, non-tumorigenic E1A/Ras-expressing IMR90 cells, these spontaneously transformed cells displayed aberrant growth potential in vitro and were capable of tumorigenesis in vivo. In contrast to the parental E1A/Ras-expressing cells, both the spontaneously transformed cells and cells derived from resultant tumors displayed specific t(7q;8q) and t(5q;17) structural chromosomal changes. Chromosome 8q contains c-Myc, which is capable of activating the telomerase catalytic subunit, hTERT. Notably, upregulation of c-Myc, hTERT, and telomerase activity were detected only in the tumorigenic cells. Transduction of Myc siRNA into the tumorigenic cells led to a concomitant down-regulation of hTERT. Furthermore, transduction of Myc or hTERT into the non-tumorigenic E1A/Ras-expressing IMR90 cells was able to confer tumorigenesis on these cells. These studies suggest that the t(7;8) translocation may result in Myc overexpression and its subsequent activation of hTERT, which may contribute to the tumorigenicity of the IMR90 cells. Furthermore, this report describes additional successful neoplastic transformation of human IMR90 fibroblasts by defined genetic elements. The spontaneously transformed cells we have derived provide a valuable model system for the study of neoplastic transformation.

Keywords: Neoplastic transformation; E1A; RAS; Myc; Telomerase.
#These two authors contributed equally
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